B lymphocytes play an important role in the pathogenesis of autoimmune diseases. Certain B-cell depleting therapeutic agents have been shown to be effective for the treatment of various autoimmune diseases, including for example, rheumatoid arthritis (RA), multiple sclerosis (MS) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
B cells mature within the bone marrow and leave the marrow expressing an antigen-binding antibody on their cell surface. When a naive B cell first encounters the antigen for which its membrane-bound antibody is specific, the cell begins to divide rapidly and its progeny differentiate into memory B cells and effector cells called plasmablasts which ultimately differentiate into plasma cells. Memory B cells have a longer life span and continue to express membrane-bound antibody with the same specificity as the original parent cell. Plasma cells do not produce membrane-bound antibody, but instead produce the antibody in a form that can be secreted. Secreted antibodies are the major effector molecules of humoral immunity.
B-cell lymphomas express a cell surface antigen, CD20, and this antigen can serve as a target of therapeutic agents for the treatment of such lymphomas. In essence, such targeting can be generalized as follows: antibodies specific to the CD20 surface antigen of B cells are administered to a patient. These anti-CD20 antibodies specifically bind to the CD20 antigen of (ostensibly) both normal and malignant B cells; the antibody bound to the CD20 surface antigen may lead to the destruction and depletion of neoplastic B cells. Thus, such anti-CD20 antibodies are known as B-cell depleting therapeutic agents.
One such anti-CD20 antibody is rituximab (RITUXAN®) antibody, which is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen. Rituximab is the antibody called “C2B8” in U.S. Pat. No. 5,736,137 (Anderson et al.). Rituximab is indicated for the treatment of patients with relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma. In vitro mechanism-of-action studies have demonstrated that rituximab binds human complement and lyses lymphoid B-cell lines through CDC (Reff et al., Blood, 83(2):435-445 (1994)). Additionally, it has significant activity in assays for ADCC. Rituximab is FDA approved for not only for therapy of diffuse large B cell lymphoma, chronic lymphocytic leukemia, but also for rheumatoid arthritis (RA) patients with previous inadequate response to TNF antagonist therapies. Importantly, rituximab spares CD20-negative early B cell lineage precursor cells and late B lineage plasma cells in the bone marrow, and treated patients usually begin to replete their peripheral blood B cell pool by 4-6 months.
Rheumatoid arthritis (RA) is a clinically important, chronic systemic autoimmune inflammatory disease affecting between 1.3 and 2.1 million persons in the United States (See, e.g., Alamanosa and Drosos, Autoimmun. Rev., 4:130-136 (2005)). RA is an autoimmune disorder of unknown etiology. Most RA patients suffer a chronic course of disease that, even with currently available therapies, may result in progressive joint destruction, deformity, disability and even premature death. More than 9 million physician visits and more than 250,000 hospitalizations per year result from RA.
Diagnosis of RA typically relies on clinical and laboratory evaluation of a patient's signs and symptoms. Generally, laboratory evaluation of a patient suspected of having RA may include determination of the level of certain antibodies in serum known as rheumatoid factor (RF) and antibodies to cyclic citrullinated peptide (anti-CCP). (See, e.g., Schellekens et al., Arthritis Rheum., 43:155-163 (2000); DiFranco et al., Rev. Rheum. Engl. Ed., 66(5):251-255 (1999); Rantapaa-Dahlqvist et al., Arthritis Rheum., 48:2741-2749 (2003); Li et al., Bioinformatics 22(12):1503-1507 (2006); Russell et al., J. Rheumatol., 33(7):1240-1242 (2006); Ota, Rinsho byori. Jap. J. Clin. Pathol., 54(8)861-868 (2006); Avouac et al., Ann. Rheum. Dis., 65(7):845-851 (2006)). While these antibodies are often found in the serum of RA patients, not all RA patients have them. An additional blood test known as the erythrocyte sedimentation rate (ESR) may also be used. An elevated ESR indicates the general presence of an inflammatory process, although not necessarily RA. Further blood tests may be used to assess the level of other factors, such as C-reactive protein (CRP), that have been associated with RA. In addition, radiographic analysis of affected joints may be performed. In sum, such currently available laboratory tests to diagnose RA are imprecise and imperfect.
In certain instances, diagnosis of RA is made if a patient satisfies certain American College of Rheumatology (ACR) criteria. Certain such criteria include morning stiffness in and around the joints lasting for at least 1 hour before maximal improvement; arthritis of three or more joint areas: at least three joint areas have simultaneously had soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician; the 14 possible joint areas (right and left) are proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, elbow, knee, ankle, and metatarsophalangeal (MTP) joints; arthritis of hand joints: at least one joint area swollen as above in wrist, MCP, or PIP joint; symmetric arthritis: simultaneous involvement of the same joint areas (as in arthritis of three or more joint areas, above) on both sides of the body (bilateral involvement of PIP, MCP, or MTP joints is acceptable without absolute symmetry); rheumatoid nodules: subcutaneous nodules over bony prominences or extensor surfaces or in juxta-articular regions that are observed by a physician; serum rheumatoid factor: demonstration of abnormal amounts of serum rheumatoid factor by any method that has been positive in fewer than five percent of normal control patients; radiographic changes: radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist X-rays, which must include erosions or unequivocal bony decalcification localized to or most marked adjacent to the involved joints (osteoarthritis changes alone do not qualify). Diagnosis of RA is typically made if a patient satisfies at least four of the above criteria.
In certain instances, a diagnosis of RA is made if a patient has a particular Disease Activity Score (DAS) (see, e.g., Van der Heijde D. M. et al., J Rheumatol, 1993, 20(3): 579-81; Prevoo M. L. et al, Arthritis Rheum, 1995, 38: 44-8). The DAS system represents both current state of disease activity and change. The DAS scoring system uses a weighted mathematical formula, derived from clinical trials in RA. For example, the DAS 28 is 0.56(T28)+0.28(SW28)+0.70(Ln ESR)+0.014 GH wherein T represents tender joint number, SW is swollen joint number, ESR is erythrocyte sedimentation rate, and GH is global health. Various values of the DAS represent high or low disease activity as well as remission, and the change and endpoint score result in a categorization of the patient by degree of response (none, moderate, good).
Multiple Sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system that affects the brain and spinal cord. MS generally exhibits a relapsing-remitting course or a chronic progressive course. Relapsing-remitting MS (RRMS) is characterized by partial or total recovery after attacks. Secondary-progressive MS (SPMS) is a relapsing-remitting course which becomes steadily progressive. Attacks and partial recoveries may continue to occur. Primary-progressive MS (PPMS) is progressive from the onset. Symptoms in patients with PPMS generally do not remit—i.e., decrease in intensity. Current treatments for MS include corticosteroids, beta interferons (BETAFERON®, AVONEX®, REBIF®), glatiramer acetate (COPAXONE®), methotrexate, azathioprine, cyclophosphamide, cladribine, baclofen, tizanidine, amitriptyline, carbamazepine (Berkow et al. (ed.), 1999, supra) and natalizumab (TYSABRI®). In addition, consistent with reports implicating B-cells in the pathogenesis of MS, rituximab has shown some clinical activity in RRMS (see, e.g., Cross et al., J. Neuroimmunol. 180:63-70 (2006) and in PPMS (see, e.g., Hawker K et al., Ann Neurol. 66(4):460-71 (2009)).
Wegener's granulomatosis and microscopic polyangiitis are classified as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides because most patients with generalized disease have antibodies against proteinase 3 or myeloperoxidase. (Jennette J C et al., Arthritis Rheum 37:187-192 (1994); Finkielman J D et al., Am J Med 120(7):643.e9-643.14 (2007)) The ANCA-associated vasculitides affect small-to-medium-size blood vessels, with a predilection for the respiratory tract and kidneys. (Hoffman G S et al., Ann Intern Med 116:488-498 (1992); Guillevin L et al., Arthritis Rheum 42:421-430 (1999); Reinhold-Keller E et al., Arthritis Rheum 43:1021-1032 (2000); Stone J H. Arthritis Rheum 48:2299-2309 (2003)). Cyclophosphamide and glucocorticoids have been the standard therapy for remission induction for nearly four decades. (Novack S N et al., N Engl J Med 284:938-942 (1971); Fauci A S et al., Medicine (Baltimore) 52:535-561 (1973)). More recently, a number of studies have shown that rituximab demonstrates clinical activity in Wegener's granulomatosis and ANCA-vasculitis. (Specks et al. Arthritis & Rheumatism, 44(12):2836-2840 (2001); Keogh et al., Kidney Blood Press. Res., 26:293 (2003); Eriksson, “Kidney and Blood Pressure Research, 26:294 (2003); Jayne et al., Kidney and Blood Pressure Research, 26:294-295 (2003); Eriksson, J. Internal Med., 257:540-548 (2005); Keogh et al., Arthritis and Rheumatism, 52:262-268 (2005); Stone et al., N. England J. Med. 363(3):221-231 (2010)).
A number of published studies in RA report the attempted identification of reliable biomarkers for diagnostic and prognostic purposes, including biomarkers that can be used to predict patient responsiveness to various therapeutic agents. (See e.g., Rioja et al., Arthritis and Rheum. 58(8):2257-2267 (2008); Pyrpasopoulou et al., Mol. Diagn. Ther. 14(1):43-48 (2010); WO 2004/0009479; WO 2007/0105133; WO 2007/038501; WO 2007/135568; WO 2008/104608; WO 2008/056198; WO 2008/132176; and WO 2008/154423). No clinically validated diagnostic markers, however, e.g., biomarkers, have been identified that enable clinicians or others to accurately define pathophysiological aspects of rheumatoid arthritis, clinical activity, response to therapy, prognosis, or risk of developing the disease. Accordingly, as RA patients seek treatment, there is considerable trial and error involved in the search for therapeutic agent(s) effective for a particular patient. Such trial and error often involves considerable risk and discomfort the the patient in order to find the most effective therapy. Thus, there is a need for more effective means for determining which patients will respond to which treatment and for incorporating such determinations into more effective treatment regimens for rheumatoid arthritis patients.
It would be highly advantageous to have additional diagnostic methods, including molecular-based diagnostic methods, that can be used to objectively identify the presence of and/or classify rheumatic disease in a patient, define pathophysiologic aspects of rheumatoid arthritis, multiple scerlosis or ANCA-vasculitis, as well as clinical activity, response to therapy, including response to treatment with various therapeutic agents, prognosis, and/or risk of developing disease. In addition, it would be advantageous to have molecular-based diagnostic markers associated with various clinical and/or pathophysiological and/or other biological indicators of disease. Thus, there is a continuing need to identify new molecular biomarkers associated with rheumatoid arthritis as well as other autoimmune disorders. Such associations would greatly benefit the identification of the presence of disease in patients or the determination of susceptibility to develop the disease. Such associations would also benefit the identification of pathophysiologic aspects of RA, MS, ANCA-vasculitis, clinical activity, response to therapy, or prognosis. In addition, statistically and biologically significant and reproducible information regarding such associations could be utilized as an integral component in efforts to identify specific subsets of patients who would be expected to significantly benefit from treatment with a particular therapeutic agent, for example where the therapeutic agent is or has been shown in clinical studies to be of therapeutic benefit in such specific patient subpopulation.
The invention described herein meets certain of the above-described needs and provides other benefits.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety for any purpose.